Usefulness of cell-penetrating peptides and penetration accelerating sequence for nose-to-brain delivery of glucagon-like peptide-2.
J Control Release
; 335: 575-583, 2021 07 10.
Article
em En
| MEDLINE
| ID: mdl-34116136
ABSTRACT
Neuropeptides are expected as therapeutic drug candidates for central nervous system (CNS) disorders. Intracerebroventricular (i.c.v.) administration of glucagon-like peptide-2 (GLP-2) has an antidepressant-like effect not only in depression model mice but also in treatment-resistant depression model mice. However, because i.c.v. administration is very invasive, research is progressing on brain delivery using intranasal administration as a non-invasive method. After intranasal administration of the drug, there are two routes to the brain. That of direct delivery from the paracellular route of olfactory epithelium to the brain via the olfactory bulb has been studied, and that of systemic absorption via the paracellular route of respiratory epithelium has been put to practical use. The high degree of vascularization and permeability of the nasal mucosa enables drug delivery via the paracellular route that leads to systemic delivery. Therefore, suppressing systemic absorption may increase drug delivery to brain, so we focused on the transcellular route. We created a GLP-2 derivative by adding cell-penetrating peptides (CPP) and penetration accelerating sequences (PAS), which are reported to provide efficient intracellular uptake, to GLP-2. However, to deliver GLP-2 by the transcellular route, GLP-2 must not only be taken up into cells but also move out of the cells. We investigated in vitro and in vivo function of PAS-CPP-GLP-2 to enable the translocation of GLP-2 directly from the nose to the brain. Derivatization of PAS-CPP-GLP-2 prevented its degradation. In the evaluation of intracellular dynamics, PAS-CPP-GLP-2 enhanced cellular uptake by macropinocytosis with CPP and promoted escape from endosomal vesicles by PAS. This study also showed that PAS-CPP-GLP-2 can move out of cells. Furthermore, only this PAS-CPP-GLP-2 showed an antidepression-like effect within 20 min of intranasal administration. Intranasal administered PAS-CPP-GLP-2 surprisingly showed the effect at the same dose with i.c.v. administration, but intravenous administered PAS-CPP-GLP-2 did not show the effect. These results suggested that PAS-CPP-GLP-2 can be efficiently delivered from the nose to the CNS and show a pharmacological effect, demonstrating the usefulness of PAS and CPP for nose-to-brain delivery of GLP-2.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos Penetradores de Células
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article